An Efficient FeCl 3 Catalyzed Synthesis of N , N ’-Diarylformamidines

An efficient FeCl3 catalyzed synthesis of N,N’-diarylformamidines using triethylorthoformate (1 equivalent) and primary aryl amines (2 equivalents) at ambient temperature has been described. This methodology provides an ecofriendly and simple procedure without using any hazardous and expensive chemicals.


Introduction
Formamidines have structural similarity to the imidazole ring, a part of the histamine molecule, are supposed to possess enormous biological activities.The biochemical aims of formamidines include monoamine oxidase inhibitor [1,2], adrenergic, neurochemical receptors [3][4][5][6][7][8] and prostaglandin E2 synthesis [9].Formamidines are also noted for their complexation with transition metals [10,11] and usage as auxiliaries in asymmetric synthesis [12,13], electrophiles [14].The utility of formamidines as support linkers in solid phase synthesis [15] is now well established in the field of organic synthesis.Formamidines are now vastly used for the preparation of imidazolium salts which are the precursor for the synthesis of N-Heterocyclic carbenes [16].Moreover, formamidines are useful subject of interest to the physical chemists for dynamic NMR study [17].There have also been reported some cryoscopic molecular weight determination experiments utilizing the molecular association property of diarylformamidines in benzene solution [18].

Results and Discussion
There are only a few reports [16,[19][20][21][22][23][24][25][26] in the literature for the synthesis of formamidines specially using triethyl orthoformate and amines.However, there is still scope for further improvement in this field since most of the reported methods suffer from long reaction times, elevated temperature or use of toxic and expensive reagents.Very recently, Sadek et al. [26] reported the synthesis of diarylformamidines using ceric ammonium nitrate (CAN) in water.But it is well known that CAN is a toxic and strong oxidizing reagent and especially in water it shows strong acidic property to affect many sensitive functional groups.So, a mild and efficient method is still desirable.We report herein an efficient FeCl 3 catalyzed synthesis of N,N'-diarylformamidines using triethylorthoformate (1 equivalent) and primary aryl amines (2 equivalents) at ambient temperature.Compared to other methods this method is much more environment friendly due to not using any toxic chemicals.In a preliminary experiment, a solution of aniline (1a) (2 mmol) and triethyl orthoformate (1 mmol) in the presence of a catalytic amount of FeCl 3 (10 mol%) in toluene (10 mL) was stirred for 3 h at room temperature.Solvent was removed and the solid mass obtained was purified by column chromatography over silica gel to afford pure formamidine 1b in excellent yield (Scheme 1).
Thus, a series of diarylformamidines have been synthesized using the reaction conditions and the results are summarized in Table 1.All the products were characterized by spectral and analytical studies and were compared with the reported data (10,13b,13d,13f-h).The probable mechanism of the formation of the product may be suggested with the line of the report by Sadek et al. [26] (Scheme 2).It is proposed that FeCl 3 as a Lewis acid activates ethoxy groups and enhances the C-O bond cleavage to generate a stable carbocation which facilitates the subsequent nucleophilic displacements by aromatic amines.

Conclusion
In conclusion, we have developed a mild and efficient method for the direct conversion of primary aryl amine to N,N'-diarylformamidines using a catalytic amount of ple method oxic and expensive reagents.

General Procedures
All melting points were taken on a Gallenkamp melting point apparatus and are uncorrected.The 1 H and 13  were recorded in CDCl 3 using TM on 300 and 75 MHz spectrome and IR were recorded using a Shim strument.High-resolution mass spectra were obtained using a Qt of Micro YA263 instrument.Toluene was dried over sodium.Chloroform was freshly distilled from phosphorus pentoxide.Petroleum ether of boiling range 60˚C -80˚C and silica gel of 60 -120 mesh were used for column chromatography.

Table 1 . Synthesis of N,N'-diarylformamidines.
a Yields refer to pure isolated products.b Refluxed in toluene.